Ghrelin gastrokinetic action in patients with neurogenic gastroparesis

Binn, Muriel; Albert, Claire; Gougeon, Alain; Maerki, Hans Peter; Coulie, Bernard; Lemoyne, Michel; Lhoret, R. Rabasa; Tomasetto, Catherine; Poitras, Pierre

doi:10.1016/j.peptides.2005.12.008

Cited by 89 publications

(74 citation statements)

References 21 publications

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“…In a randomized, doubleblind, cross-over study, administration of a ghrelin infusion increased GE of a 330 kcal ricepudding test meal in seven of ten patients with diabetic gastroparesis and this effect was independent of vagal tone [73]. Similar results have been found in a study of six patients with idiopathic gastroparesis with enhanced GE and decreased meal-related symptom scores [74] as well as patients with neurogenic gastroparesis using bolus doses of 1 or 4 μg/kg of ghrelin to suggest extravagal prokinetic actions of ghrelin [75].…”

Section: Current Clinical Trials Of Ghrelin Agonists In Gastroparesissupporting

confidence: 75%

“…In addition, responsiveness to treatment with ghrelin agonists among patients with gastroparesis may vary depending on the underlying etiology of the disease and further study among patients with post-surgical and idiopathic gastroparesis will need to be explored. Although actions of ghrelin appear to be mediated mainly through vagal signaling or directly via the enteric nervous system [19], extravagal effects of ghrelin on gastric motility have been show in patients with neurogenic causes of gastroparesis [75]. Furthermore, it has been suggested that there exists potential for desensitization of the ghrelin receptor with repeated dosing; however, in a study of co-administration of acylated and unacylated ghrelin no tachyphylaxis was observed with repeated administration in inducing decreased insulin concentrations [95].…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Shin

2015

Curr Gastroenterol Rep

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There remains an unmet need for effective pharmacologic treatments for gastroparesis.Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101 initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM-131 was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis.

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Section: Current Clinical Trials Of Ghrelin Agonists In Gastroparesissupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Shin

2015

Curr Gastroenterol Rep

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“…The limitations of this study design include the lack of chronic efficacy data beyond two weekly infusions; namely, body composition (lean body mass, fat mass (Theander-Carrillo et al, 2006)), objective subconscious locomotive motor and physical activity (Jaszberenyi et al, 2006), energy expenditure measurements (Lejeune et al, 2006), and gastrointestinal motility (Binn et al, 2006;Blom et al, 2006). Our results on dose responsiveness may be influenced by unbalanced groups: UD patients had more metastases, greater weight loss, lower dietary intake, more early satiety, and were closer to death.…”

Section: Intravenous Ghrelin For Cancer Anorexia/cachexia F Strasser mentioning

confidence: 99%

“…The safety and tolerability data support further exploration of the therapeutic potential of natural ghrelin, namely escalation of dose and frequency and chronic administration. The patient population may be stratified for baseline ghrelin levels (Garcia et al, 2005;Wolf et al, 2006), and other factors need to be controlled for, namely genetic alterations of the ghrelin gene (Holst and Schwartz, 2006), cytokine levels (Dixit et al, 2004), stress level (Kristenssson et al, 2006), hypogonadism (Strasser et al, 2006), patients' eating preferences (Blom et al, 2006), baseline food intake (Gilg and Lutz, 2006), and gastric emptying (Binn et al, 2006). These strategies may counteract the series of many negative cachexia phase III trials (EPA, cannabinoids) or single not confirmed studies (ATP, thalidomide), treating uniformly all patients having loss of weight and appetite, despite promising pathophysiological concepts.…”

Section: Intravenous Ghrelin For Cancer Anorexia/cachexia F Strasser mentioning

confidence: 99%

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

Strasser¹,

et al. 2008

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Twenty-one adult patients were randomised to receive ghrelin on days 1 and 8 and placebo on days 4 and 11 or vice versa, given intravenously over a 60-min period before lunch: 10 received 2 mg kg À1 (lower-dose) ghrelin; 11 received 8 mg kg À1 (upper-dose) ghrelin. Active and total ghrelin, growth hormone (GH), and insulin-like growth factor 1 levels were monitored at baseline (4 -5 days before day 1), during treatment days, and at end of study (day 17/18). Drug-related adverse events (assessed by NCI-CTC-toxicity criteria and cardiac examination) did not differ between ghrelin and placebo. No grade 3/4 toxicity or stimulation of tumour growth was observed. The peak increase of GH, a biological marker of ghrelin action, was 25 ng ml À1 with lower-dose and 42 ng ml À1 with upper-dose ghrelin. Morning fasting total ghrelin levels were higher (Po0.05) for upper-dose patients at end of study (3580 pg ml À1 ) than at baseline (990 pg ml À1 ). Insulin-like growth factor 1 levels did not change. At day 8, 81% of patients preferred ghrelin to placebo as against 63% at the end of study. Nutritional intake and eating-related symptoms, measured to explore preliminary efficacy, did not differ between ghrelin and placebo. Ghrelin is well tolerated and safe in patients with advanced cancer. For safety, tolerance, and patients' preference for treatment, no difference was observed between the lower-and upper-dose group.

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“…Subsequently, Moechars et al (2006) suggested that the rate of gastric emptying is increased in GPR39 knockout mice, an observation which may be consistent with a gastric regulatory function for obestatin. Interestingly, this ability of obestatin to reduce gastric emptying is the opposite to the prokinetic stimulator function of ghrelin, widely shown to increase gastric emptying rate in a number of mammalian species, including humans (Murray et al, 2005;Tack et al, 2005;Binn et al, 2006;Levin et al, 2006), dogs (Trudel et al, 2003) and rodents (Asakawa et al, 2001;Trudel et al, 2002;Levin et al, 2005). This opposing activity of two proteins apparently derived from the same precursor gene, was further demonstrated by the ability of obestatin to inhibit the increased spontaneous contractility caused by ghrelin in the mouse isolated jejunum, in the absence of any direct interaction with the ghrelin binding site (Zhang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract

Bassil

Häglund

Brown

et al. 2007

British J Pharmacology

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Background and purpose: Obestatin, encoded by the ghrelin gene may inhibit gastrointestinal (GI) motility. This activity was re-investigated. Experimental approach: Rat GI motility was studied in vitro (jejunum contractility and cholinergically-mediated contractions of forestomach evoked by electrical field stimulation; EFS) and in vivo (gastric emptying and intestinal myoelectrical activity). Ghrelin receptor function was studied using a GTPgS assay and transfected cells. Key results: Contractions of the jejunum or forestomach were unaffected by obestatin 100 nM or 0.01-1000 nM, respectively (P40.05 each; n ¼ 4-18). Obestatin (0.1-1 nM) reduced the ability of ghrelin 1 mM to facilitate EFS-evoked contractions of the stomach (increases were 42.777.8% and 21.275.0 % in the absence and presence of obestatin 1 nM; Po0.05; n ¼ 12); higher concentrations (10-1000 nM) tended to reduce the response to ghrelin but changes were not statistically significant. Similar concentrations of obestatin did not significantly reduce a facilitation of contractions caused by the 5-HT 4 receptor agonist prucalopride, although an inhibitory trend occurred at the higher concentrations (increases were 69.3714.0% and 42.678.7% in the absence and presence of 1000 nM obestatin; n ¼ 10). Obestatin (up to 10 mM) did not modulate recombinant ghrelin receptor function. Ghrelin increased gastric emptying and reduced MMC cycle time; obestatin (1000 and 30,000 pmol kg À1 min À1 ) had no effects. Obestatin (2500 pmol kg À1 min À1 , starting 10 min before ghrelin) did not prevent the ability of ghrelin (500 pmol kg À1 min À1 ) to shorten MMC cycle time. Conclusions and implications: Obestatin has little ability to modulate rat GI motility.

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Ghrelin gastrokinetic action in patients with neurogenic gastroparesis

Cited by 89 publications

References 21 publications

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

Little or no ability of obestatin to interact with ghrelin or modify motility in the rat gastrointestinal tract

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